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Geoffrey Shapiro, MD, PhD

A two-time Lymphoma Research Foundation (LRF) grant recipient, Geoffrey Shapiro, MD, PhD has built his career as a solid tumor oncologist studying new therapeutic agents that have greatly improved the lives of people with mantle cell lymphoma (MCL) as well as other diseases. In 2003, he was one of the first researchers to receive the LRF Mantle Cell Lymphoma Initiative grant to research a class of drugs called cyclin-dependent kinase (cdk) inhibitors in mantle cell lymphoma cell lines. Then, in 2007, he was awarded the Mantle Cell Lymphoma Correlative grant to study therapeutic agents in this class, including PDO332991and Flavopiridol, in MCL clinical trials.

Geoffrey Shapiro, MD, PhD

The biology of MCL is such that the disease has the potential to respond to members of the cdk-inhibitor drug class. Dr. Shapiro, having spent most of his career studying cdk-inhibitors, chose to work in the field of MCL so that his research could have the greatest impact possible.

"Mantle cell lymphoma is a lymphoma subset for which new treatment approaches are needed," said Dr. Shapiro. "I saw the opportunity to apply this class of drugs to mantle cell lymphoma and wanted very much to work in an area where these agents have great potential. The success of many novel targeted agents, including mTOR inhibitors, PI3K inhibitors, as well as cdk inhibitors in lymphomas, especially in subpopulations in great need of new approaches, has stimulated me to want to continue in early drug development that will be applicable across cancers."

Dr. Shapiro recently presented the results of a multi-institutional clinical trial partially funded by his MCL Correlative grant at LRF's Mantle Cell Lymphoma Eighth Annual Scientific Workshop in March. After treating 17 people with advanced/refractory MCL with the cdk4 inhibitor PDO332991, one person achieved a complete response and two had partial responses. Five patients were able to stay on the drug for more than a year without a worsening of their disease. Ultimately, they "demonstrated that PD0332991 potently blocks the activity of cdk4, the key protein driving the growth of mantle cell lymphoma cells," he said.

This trial was able to open doors for future research on PD0332991 and other cdk inhibitors. Already, similar trials are being conducted in breast and lung cancer as well as gastrointestinal malignancies, and researchers at Weill-Cornell Medical College are developing drug combinations with PD0332991 with the potential to make a difference in lives of people with lymphoma.

"The successful demonstration of cdk4 inhibition in patients' tumors by this drug, as well as the promising clinical results, has stimulated more work with this agent," he explained. "Before our work, there was a possibility that this agent would be shelved."

In addition to this trial, Dr. Shapiro has also been investigating why cdk inhibitors are not always successful in mantle cell lymphoma. "We are currently studying the mechanisms by which mantle cell lymphoma cells can become resistant to a cdk4 inhibitor," he said. "We are also trying to assess baseline characteristics of the lymphoma cells that predict whether there will be long-term benefit from cdk4 inhibition or rapid development of resistance."

Dr. Shapiro is grateful for the opportunity to participate in LRF's Mantle Cell Lymphoma Consortium (MCLC) and for the research funding and partnerships that have come out of networking within the organization.

"Via interactions initiated within the MCLC, I have had the opportunity to collaborate with colleagues from the National Cancer Institute on the development of other drugs that target cdks," he said. "The preclinical and clinical testing of cdk inhibitors would not have been possible without LRF funding. In particular, the MCL correlative grant facilitated the research that helped prove that PD0332991 effectively blocks cdk4 in patients' lymphomas."

When asked for his best advice to a newly diagnosed lymphoma patient, Dr. Shapiro said remaining optimistic about lymphoma research is crucial.

"This is a hopeful time in which there is better understanding of lymphoma biology and during which treatments are increasingly successful," he stressed. "Because of the complexity of the disease, with different strategies for different disease subsets, consultation with an oncologist highly experienced in lymphoma treatment is important."

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